Three general routes have been developed for the synthesis of cyano-substituted-nitrogen containing heteroaryl compounds. These are illustrated below in Schemes 1a, b and c.
Scheme 1. Synthesis of Cyano-Substituted Nitrogen Containing Heteroaryl Compounds.
a. Cyclization of Acyclic Precursors
b. Synthesis by Functional Group Introduction
c. Synthesis by Functional Group Interchange

Cyano-substituted-nitrogen-containing heteroaryl compounds are valuable chemical intermediates for the preparation of a number of drugs. For example, 3-cyano-1H-1,2,4-triazole (3-CNT) is a key intermediate in the preparation of Ribavirin, which is used in treating Hepatitis C (see, U.S. Pat. Nos. 3,927,216 and 4,138,547). 4-Cyanoimidazole is key intermediate in the preparation of both pharmaceuticals and agrochemicals as well as crosslinking agents for epoxy resins (see, Less et al., Inorg. Chem. 2004, Japanese Patent No. 06073018). 2-Cyanopyrazine is key intermediate in the preparation of anti-microbial agents (see, Johnston et al., U.S. Pat. Nos. 4,442,095, 4,442,096 and 4,442,097; Beutel et al., U.S. Pat. No. 3,555,021); anti-inflammatory agents (see, U.S. Pat. No. 4,778,890; Opletalova et al., Coll. Czech. Chem. Comm. 61(7): 1093-11-01 (1996); and anti-tuberculosis drugs (see Indian Patent Nos. 177,142; 182,184; 182,185 and 185,265; Foks and Sawlewicz Acta Polonia Pharmaceutica 25(2): 137-42 (1968)). As discussed in more detail below, various synthetic routes for these useful intermediates have been reported in literature. Unfortunately, these molecules are often difficult to be produced on a large scale by known synthetic methods.
Cyanotriazoles
Few routes have been published in the literature for the synthesis of 3-CNT and these have not been commercialized. Using the first method, 3-CNT is manufactured beginning with cyanogen and anhydrous hydrazine as illustrated generally above in Scheme 1a. However, this method has several drawbacks including a) the toxicity of the starting material, cyanogen, which is currently commercially not available, b) the inconsistent and low yields obtained and c) the need for a laborious recrystallization step to achieve high purity. In addition, the hazards of handling anhydrous hydrazine are well documented in literature.
In another method, one is able to manufacture 3-CNT beginning with 3-chloro-1,2,4-triazole and sodium cyanide as illustrated generally above in Scheme 1c (see, U.K. Patent No. 1,157,256). However this method also has several drawbacks including a) limited supply of the starting material, 3-chloro-1,2,4-triazole, b) the high reaction temperature (150-160° C.) which results in mixture of products which is difficult to work up, and c) low isolated yields.
Cyanoimidazoles
Likewise, multiple routes have been published in the literature for the synthesis of 4(5)-cyanoimidazoles and these have not been commercialized. Methods for preparing cyanoimidazoles are generally reviewed in M. R. Grimmett Science of Synthesis 12: 325-528 (2002). Some of these are discussed in more detail below.
Enaminonitriles have been cyclized into imidazole 4-carbonitrile (see, Ferris and Trimmer, J. Org. Chem. 41(1): 19-24 (1976)). Cyano groups can be introduced onto imidazoles by reacting imidazoles with carbon tetrahalides in liquid ammonia (see, Japanese Patent 59227852). In addition, 4(5)-cyanoimidazoles can be prepared by decarboxylation of cyanoimidazole carboxylic acids by heating, often in the presence of phosphonium or ammonium salt catalysts, such as tetrabutylphosphonium bromide; alkali or alkali earth metal salts, such as lithium chloride (see, Japanese Patent Nos.: 2002322158 and 2002371068); or sequential treatment with metal complexes in protic solvents, alkali hydroxides, ammonia, copper sulfate and sodium hydroxide (see, Japanese Patent Nos.: 03197465 and 2869118). Cyanoimidazoles can be prepared by dehydrating oxime imidazoles with heating in the presence of Ac2O (see, Japanese Patent Nos.: 62175471 and 2562872 and Kawakami et al. Synthesis 5: 677-680 (2003)). 4(5)-cyanoimidazole can also be prepared by treating 4(5)-trifluoromethylimidazole with 5% NH4OH (see, Matthews et al. J. Org. Chem. 51(16): 3228-31 (1986)), although the starting material is not readily available. Finally, 4(5)-cyanoimidazole has been prepared from 4(5)-imidazolecarboxaldehyde and 4(5)-thiocarbamoylimidazole, although similarly, both starting materials are not readily available. Of the various other synthetic routes leading to 4-cyanoimidazole described in literature, none are cost effective methods.
Cyanopyrazines
Multiple routes have been published in the literature for the synthesis of 3-cyanopyrazines and these have not been commercialized. Methods for preparing cyanoimidazoles are generally reviewed in N. Sato, Science of Synthesis 16: 751-844 (2004). Some of these are discussed in more detail below.
2-Cyanopyrazine was prepared by oxidation of 2-methylpyrazine with ammonia in the presence of various catalysts. The drawbacks of these method include their requiring a) a specially prepared catalyst, b) a pressure reactor to contain ammonia and oxygen and/or c) high reaction temperatures (>350° C.). (see, Rao et al. Cat. Lett 68(3, 4): 223-227 (2000); Green, Chem. 3(1): 20-22 (2001); Rao et al., Chemical Communications 20: 2088-89 (2001); Rao et al., Indian Patent No. 185,265; Reddy et al., Indian Patent Nos. 182,184 and 182,185; Chinese Patent Nos: 1,398,855 and 1,398,856; Srilakshmi et al., Cat. Lett. 83(3-4): 127-32 (2002); Bondareva et al, Kinetics and Catalysis 45(1): 104-113 (2004); 41(5): 670-678 (2000); 41(2): 222-230 (2000); 38(5): 657-661 and 662-668 (1997); Reaction Kinetics and Catalysis Letters 79(1): 165-173 (2003); Catalysis Today 61(1-4): 173-178 (2000); Catalysis Lett. 42(1, 2): 113-118 (1996); Feng et al. Gaoxiao Huaxue Gongcheng Xuebao 17(4): 395-399 (2003); Gupta et al. Indian Patent No. 177,142; Jin et al Jingxi Huagong 19(6) (2002); Sasaki et al. Applied Cat., A: General 194-195: 497-505 (2000) and U.S. Pat. No. 6,392,048); Shin et al. Chem. Technol. Res. Div. 8(5): 749-755 (1997); Gusejnov et al. Russian Patent No. 2061689; Lee et al. U.S. Pat. Nos. 5,786,478 and 6,013,800 and Korean Patent Nos. 151820; Reddy et al. Chem. Ind. 62: 487-491 (1995); Lempers et al. Inorganica Chimica Acta 225(1-2)67-74 (1994); Wang et al. Tianranqi Huagong 18(5): 45-9 (1993); S. Shimizu, Shkubai 35(1): 22-6 (1993); Petrotech 15(6): 514-18 (1992), U.S. Pat. Nos. 4,778,890 and 4,931,561; Kwon et al Taehan Hwahakhoe Chi 34(5): 445-51 (1990); Husain et al. J. Chrom 513: 83-91 (1990); L. Forni J. Chem. Soc., Faraday Trans 1: Physical Chem. Condensed Phases 84(7): 2397-407 (1988); Applied Catalysis 20(1-2):219-30 (1986); Abe et al. Japanese Patent No. 63,010,753; Bergstein et al. U.S. Pat. Nos. 4,419,272 and 4,496,729); Okada et al. Yakugaku Zasshi 98(11); (1978); Kajiyama et al. Japanese Patent No. 49030382; Beutel et al. U.S. Pat. No. 3,555,021; Srilaxmi et al. (Catalysis Comm. 5: 199-203 (2004); and Narashima et al. (Chem. Comm. 20: 2088-2089 (2001).
In addition, Cao et al. (see, Syn. Comm. 31(14): 2203-2207 (2001)) describe treating halo-pyrazines neat with sodium cyanide and a phase transfer catalyst. Jose et al. (see Syn. Comm. 30(8): 1509-1514 (2000)) describe dehydrating aldoximes with Burgess reagent. Sato et al. (see, J. Chem. Soc. Perkin Trans I 11: 2877-81 (1991)) describe treating 3-substituted pyrazine 1-oxides with TMSCN or (EtO2)POCN and triethylamine, optionally in the presence of ZnBr2. This method gives mixtures of products in low yields.
Finally, Zergenyi et al. (European Patent No. 122355) describes treating fluoropyrazine with Me2SO and NaCN to give pyrazinecarbonitrile. Hardt et al. (see, J. Analytical and Applied Pyrolysis 13(3): 191-8 (1988)) describe pyrolyzing polyhydroxyalkylpyrazines with ammonia to give multiple pyrazine products.
Carboxamide to Nitrile Conversions
A common strategy to prepare other nitrile-substituted compounds is to start with the corresponding carboxamide (for reviews see, Chem. Rev. 42:189 (1948); Z. Chem. 22: 126 (1982)). The carbonyl oxygen can be dehydrated by a number of reaction conditions to form the nitrile functionality as illustrated below in Table 1.
TABLE 1Formation of Nitriles from CarboxamidesReaction Conditions (Reagents, Solvents, Temperature, Time, etc.)ReferenceSOCl2 in DMFJ. Am. Chem. Soc. 69: 2663 (1947)J. Am. Chem. Soc. 82: 2498 (1960)J. Am. Chem. Soc. 83: 2354 (1961)J. Am. Chem. Soc. 83: 2363 (1961)J. Org. Chem. 27: 4608 (1962)Org. Syn. 4: 436 (1963)J. Org. Chem. 24: 26 (1959)J. Org. Chem. 36: 3960 (1971)J. Org. Chem. 50: 2323 (1985)Tetrahedron. 21: 2239 (1965)J. Am. Chem. Soc. 88: 2025 (1966)ClSO3NCO, Et3NChem. Comm. 227 (1979)PhSO2Cl in pyridineJ. Chem. Soc. 763 (1946)J. Am. Chem. Soc. 77: 1701 (1955)TsCl, pyridineJ. Am. Chem. Soc. 77: 1701 (1955)BSCF 2262 (1965)Sulfurous acid dipyridin-2-yl Tet. Lett. 27: 1925 (1986)ester(CF3CO)2O, pyridineTet. Lett. 1813 (1977)P2O5 with Me3SiOSiMe3J. Org. Chem. 27: 4608 (1962)Org Synthesis 4(144): 486 (1963)Synthesis 591 (1982)(Ph3PO3SCF3)O3SCF3Tetrahedron Lett. 277 (1975)(EtO)2POP(OEt)2J. Am. Chem. Soc. 88: 2025 (1966)(EtO)3PI2Tetrahedron Lett. 1725 (1979)2,2,2-Trichloro-1,3-dioxa-2λ5-J. Am. Chem. Soc. 88: 2025 (1966)phosphaindane, pyridine2-Chloro-[1,3,2]dioxa-Ber. 96: 1387 (1963)phospholanePOCl3 in DMF, DMF/pyridine J. Am. Chem. Soc. 65: 2471 (1943)or CH2ClCH2ClJ. Am. Chem. Soc. 70: 3316 (1948)J. Org. Chem. 27: 4608 (1962)J. Org. Chem. 50: 5451 (1985)U.S. Pat. No. 2,389,217U.S. Pat. No. 4,619,991Syn. Comm. 10: 479 (1980)Org Syn. 3 535 (1955)PPh3, CCl4Tetrahedron Lett. 4383 (1970)Ber. 104: 1030 (1971)Ph2P-polymer, CCl4Syn. 41 (1977)(PNCl2)3Can. J. Chem. 50: 3857 (1972)P(NEt2)3Chem. Lett. 577 (1973)COCl2, pyridine with DMFJ. Chem. Soc. 3730 (1954)Syn. Comm. 10: 479 (1980)ClCOCOCl, DMF, pyridineSyn. Comm. 10: 479 (1980)ClCO2MeBull. Acad. Polon. Sci.,Ser. Sci.Chem. 10: 227 (1962)Cl3CCOCl, Et3NSynthesis 184 (1985)Cl3COCOCl, OP(OMe)3Tetrahedron Lett. 27: 2203 (1986)Cl3CN═CCl2Synthesis 599 (1972)NaCl•AlCl3, ΔJ. Am. Chem. Soc. 62: 1432 (1940)cat. ClRh(PPh3)3Tetrahedron Lett. 1963 (1970)TiCl4/R3NTetrahedron Lett. 1501 (1971)HCCl3, NaOH, PhCH2NEt3)+Cl−Tetrahedron Lett. 2121 (1973)HN(SiMe2)3 or 4J. Org. Chem. 35: 3253 (1970)2,4,6-Trichloro-1,3,5-Synthesis 657 (1980)triazine, DMFDCC, pyridineJ. Org. Chem. 26: 3356 (1961)J. Org. Chem. 36: 3960 (1971)J. Am. Chem. Soc. 88: 2025 (1966)LiAlH4Can. J. Chem. 44: 2113 (1966)
These include commercial scale processes using thionyl chloride (SOCl2), phosphorous oxychloride (POCl3) or trifluoroacetic acid anhydride (TFAA) in solvents such as DMF and pyridine to convert the carboxamide to the corresponding nitrile (see Table 1). For instance, dehydration of cyanoacetamide with POCl3 in ethylene dichloride or benzene produces malonitrile in 70-80% yield (see, Surrey, et al., U.S. Pat. No. 2,389,217). However, the commercial dehydration of carboxamide substituents on nitrogen-containing heteroaryl compounds using these methods presents serious challenges. Most notable is general insolubility of these starting materials in solvents compatible with the dehydrating agents and by-products formation. For instance, dehydration of 5-amino-4-carboxamido-1,2,3-triazole with POCl3 in DMF requires protection of the 5-amino group and the 1-N of the triazole to effect the dehydration in 60% yield (see Mattzinger, et al., U.S. Pat. No. 4,619,991). Likewise dehydration of 4(5)-imidazole-carboxamide uses dichlorophenylphosphine oxide as a dehydrating agent to give 4-cyanoimidazole (see Leone-Bay and Glaser Syn. Comm. 17(12): 1409-12 (1987)). Dichlorophenylphosphine oxide is not readily available and is relatively expensive. Finally, dehydration of pyrazineamide uses neat phosphoryl chloride as a dehydrating agent to give 2-cyanopyrazine (see, Johnston U.S. Pat. No. 4,442,097). No solvent is used.
In contrast, the preparation of cyano-substituted-nitrogen-containing heteroaryl compounds is much more difficult. This is mainly due to the poor solubility of carboxamide-substituted nitrogen-containing heteroaryl compounds in typical dehydration solvents. Slight increase in the yield is achieved when the reaction solvent is MEK as compared with no solvent. Other dehydration agents, such as SOCl2 and trifluoroacetic anhydride, etc., under a variety of reaction conditions, also fail to provide product in reasonable yields (ca. >20%). In fact, a perusal of the literature supports the observation that the use of substrate insoluble solvents reduces the yield.
In addition, the quality of the products are sensitive to conditions for its formation, including the scale of the reaction. This in turn has an impact on the quality and yield of the final products which is important for launch of a compound to market.
What is needed in the art are methods that allow one to reliably produce cyano-substituted-nitrogen-containing heteroaryl compounds from carboxamide-substituted-nitrogen-containing heteroaryl compounds in one step and in high yields without laborious purification. Quite surprisingly, the present invention fulfills these and other needs.